Tumor Necrosis Factor-α (TNF-α), a pleiotropic cytokine, is produced mainly by macrophages, but other types of cells also produce it. TNF-α demonstrates beneficial as well as pathological activities. It has both growth stimulating effects and growth inhibitory properties, besides being self-regulatory. The beneficial functions of TNF-α include maintaining homeostasis by regulating the body's circadian rhythm, mounting an immune response to bacterial, viral, fungal and parasitic infections, replacing or remodeling injured tissue by stimulating fibroblast growth and, as the name suggests, killing certain tumors.
TNF-α has been implicated as a mediator in inflammatory bowel disease, inflammation, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, osteoarthritis, refractory rheumatoid arthritis, chronic non-rheumatoid arthritis, osteoporosis/bone resorption, Crohn's disease, septic shock, endotoxic shock, atherosclerosis, ischemia-reperfusion injury, coronary heart disease, vasculitis, amyloidosis, multiple sclerosis, sepsis, chronic recurrent uveitis, hepatitis C virus infection, malaria, ulcerative colitis, cachexia, psoriasis, plasmocytoma, endometriosis, Behcet's disease, Wegenrer's granulomatosis, AIDS, HIV infection, autoimmune disease, immune deficiency, common variable immunodeficiency (CVID), chronic graft-versus-host disease, trauma and transplant rejection, adult respiratory distress syndrome, pulmonary fibrosis, recurrent ovarian cancer, lymphoproliferative disease, refractory multiple myeloma, myeloproliferative disorder, diabetes, juvenile diabetes, meningitis, ankylosing spondylitis, skin delayed type hypersensitivity disorders, Alzheimer's disease, systemic lupus erythematosus and allergic asthma. Much research has been conducted to study the effect of TNF-α and anti-TNF-α therapies. Studies in the area of cancer have shown that with TNF-α therapy it is important to balance the cytotoxicity and systemic toxicity of the potential drug candidates.
Inflammation is the response of a tissue to injury that may be caused by invading parasites, ischemia, antigen-antibody reactions or other forms of physical or chemical injury. It is characterized by increased blood flow to the tissue, causing pyrexia, redness, swelling, and pain. Each stimulus elicits a characteristic response that has a common theme. Inflammation occurs in three distinct phases:                1. an acute transient phase characterized by local vasodilation and increased capillary permeability;        2. a subacute phase characterized by infiltration of the site by leucocytes and phagocytic cells; and        3. a chronic proliferative phase characterized by tissue degeneration and fibrosis. The recruitment of inflammatory cells to sites of injury involves the concerted interactions of several types of mediators.        
Several cytokines, especially IL-1 (interleukin-1) and TNF-α (tumor necrosis factor-α), play an important role in the inflammatory process. Both IL-1 and TNF-α are derived from mononuclear cells and macrophages and in turn induce the expression of a variety of genes that contribute to the inflammatory process. An increase in TNF-α synthesis/release is a common phenomenon during the inflammatory process. Inflammation is an inherent part of various disease states like rheumatoid arthritis, Crohn's disease, septic shock syndrome, atherosclerosis, among other clinical conditions.
Rheumatoid arthritis (RA)—an autoimmune disorder, is a chronic, systemic, articular inflammatory disease of unknown etiology. In RA, the normally thin synovial lining of joints is replaced by an inflammatory, highly vascularized, invasive fibrocollagenase tissue (pannus), which is destructive to both cartilage and bone. Areas that may be affected include the joints of the hands, wrists, neck, jaw, elbows, feet and ankles. Cartilage destruction in RA is linked to aberrant cytokines and growth factor expression in the affected joints.
The most common rheumatoid arthritis therapy involves the use of nonsteroidal anti-inflammatory drugs (NSAIDs) to alleviate symptoms. However, despite the widespread use of NSAIDs, many individuals cannot tolerate the doses necessary to treat the disorder over a prolonged period of time. In addition, NSAIDs merely treat the symptoms of disorder and not the cause.
When patients fail to respond to NSAIDs, other drugs such as methotrexate, gold salts, D-penicillamine and prednisone are used. These drugs also have significant toxicities and their mechanism of action remains unknown.
TNF-α is considered to be at the apex of the proinflammatory cytokine cascade. Elevated circulating TNF-α levels and expression of other proinflammatory mediators are diminished by anti-TNF-α treatment, indicating possible beneficial effects this treatment can offer. Intervention of TNF-α activity can occur at the synthesis, release and receptor levels. Anti-TNF-α monoclonal antibodies, soluble receptors or receptor fusion proteins will target the TNF-α receptors/binding. Synthesis of TNF-α can also be suppressed by drugs/agents such as cyclosporine A, glucocorticoids or interleukin-10.
There are several small molecules, which inhibit the production of inflammatory cytokines and have demonstrated activity in animal rheumatoid arthritis models. Potential advantages of small molecules are that they are convenient to use for chronic problems, might facilitate tissue penetration, can be used in combination with other anti-inflammatory therapies. Such molecules are in various stages of preclinical and clinical development (Nature Reviews, 2003, 2, 736-746).
US 2003/0171585 describes tricyclic compounds (triphenylpropanamides) as anti-inflammatory agents.
JP 08-119920 describes tricyclic compounds (anilide derivatives) as steroid 5α-reductase inhibitors useful in the treatment of prostate cancer, baldness and syphilis.
JP 11-130772 describes nitrogen-containing tricyclic compounds as leukocyte activation inhibitors that are useful for the treatment of inflammatory and allergic diseases.
JP 90-40662 describes tricyclic compounds that are substance P and bradykinin antagonists and are useful for the treatment of many diseases, including inflammation.
J. Med. Chem., 1970, Vol. 13, no. 4, 713-722, describes derivatives of 5, 11-dihydrodibenz[b,e][1,4]oxazepine showing anti-anxiety and CNS depressant activities.
Monoclonal antibody drugs such as Infliximab, Etanercept and Adalimumab are useful as anti-inflammatory agents, but have drawbacks such as route of administration (only parenteral), high cost, allergy induction, activation of latent tuberculosis, increased risk of cancer and congestive heart disease.
There is a need for improved and alternative medicaments for the prevention and treatment of inflammatory disorders caused by increased TNF-α activity.